Gemcitabine, a water soluble analogue of deoxycytidine, is an antineoplastic agent of difluoronucleotides by destroying cellular duplications, and a substitution in consistent with substrates activated by ribonucleotide reductases, which are vital in the syntheses of desired deoxynucleotides during the process of DNA synthesizing and repairing.
Gemcitabine is 2′-deoxy-2′,2′-difluorocytidine, and its chemical structure is the following:

Hertel et al firstly disclosed the gemcitabine compound in the U.S. Pat. No. 4,808,614 and described the preparing scheme thereof:

In the scheme, only the step of synthesizing ethyl 2,2-difluoro-3-hydroxy-3-(2,2-dimethyl-dioxolan-4-yl)-propionate involved applying silica gel column chromatography to separate the 3-R-hydroxy product, the reactions of the following steps had not been involved to the stereochemistry.
Chou Ta-Sen described another preparing scheme in U.S. Pat. No. 5,401,861 and European patent No. 0577303, in which, alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di-O-benzoyl-methanesulfonate was firstly prepared, then yielded beta-anomer enriched gemcitabine. The characteristic of the reaction for preparing alpha-anomer enriched methanesulfonate intermediate proceeded in the lower temperature (−78° C.), followed by reacting with more than 3-20 times (mols) of silyl protected cytosine, to stereoselectively produce beta-anomer enriched gemcitabine product. It should be noted that only benzoyl was disclosed as 3,5-hydroxyls protected group in these two patents. Furthermore, the reaction for preparing alpha-anomer enriched methanesulfonate was achieved in very low temperature, a more rigorous reaction condition, which is not suitable for large scale industrial application.
In addition, Lee Jaeheon et al disclosed the following scheme for preparing the intermediates in the patent international application WO2006/009353:

Moreover, Lee Jaeheon et al described the following scheme in the patent international application WO2006/011713:

Wherein, P1 is Bz or BiPhC(O)—, P2 is —P(O)(OPh)2. The alpha-anomer enriched halogenated intermediates were achieved by the above-mentioned reactions, and provided useful intermediates for stereoselectively preparing gemcitabine. However, it is found by our experiments that, in the said process of WO2006/009353, the work-up procedure of the prepared potassium salts compound requires the organic solvent of reactant solution to be rapidly concentrated to dryness under the low temperature, otherwise the product (potassium salt) would be seriously decomposed. This would affect the purity and yield, which would be too difficult to be achieved in the industrial operations. Furthermore, the excessive amount of toxic hydrogen halides that were needed in the halogenation process, posed safety problem to workers' labor protection, difficulty of handling the wastes, and vulnerability to environmental pollution.
In conclusion, the processes for preparing gemcitabine in the prior art are still insufficient as mentioned above. At present, a big demand is in need to develop a highly stereoselective process for preparing gemcitabine, in which the reaction conditions are mild and friendly to the environment.